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A Randomized Controlled Trial

David D. Waters, MD; Edwin L. Alderman, MD; Judith Hsia, MD; Barbara V. Howard, PhD; Frederick R. Cobb, MD; William J. Rogers, MD; Pamela Ouyang, MD; Paul Thompson, MD; Jean Claude Tardif, MD; Lyall Higginson, MD; Vera Bittner, MD; Michael Steffes, MD, PhD; David J. Gordon, MD, PhD; Michael Proschan, PhD; Naji Younes, PhD; Joel I. Verter, PhD

JAMA. 2002;288:2432-2440.

Context  Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, but no clinical trials have demonstrated benefit to support their use.

Objective  To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography.

Design, Setting, and Patients  The Women's Angiographic Vitamin and Estrogen (WAVE) Trial, a randomized, double-blind trial of 423 postmenopausal women with at least one 15% to 75% coronary stenosis at baseline coronary angiography. The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada.

Interventions  Patients were randomly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily, or placebo.

Main Outcome Measure  Annualized mean (SD) change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome.

Results  The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P = .17); and for antioxidant vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P = .32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P = .045), and suggested an increased risk in the active vitamin group (P = .09). Fourteen patients died in the HRT group and 8 in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and 6 in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the 2 treatment interventions.

Conclusion  In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.

Author Affiliations: Division of Cardiology, San Francisco General Hospital and the University of California, San Francisco (Dr Waters); Cardiovascular Medicine Division, Stanford University, Stanford, Calif (Dr Alderman); Departments of Medicine (Dr Hsia) and Statistics (Drs Younes and Verter), George Washington University, Washington, DC; Department of Cardiology, Medstar Research Institute, Washington, DC (Dr Howard); Duke Center for Living, Duke University, Durham, NC (Dr Cobb); Division of Cardiology, University of Alabama, Birmingham (Drs Rogers and Bittner); Division of Cardiology, Johns Hopkins Bayview Medical Center, Baltimore, Md (Dr Ouyang); Division of Cardiology, Hartford Hospital, Hartford, Conn (Dr Thompson); Montreal Heart Institute, Montreal, Quebec (Dr Tardif); University of Ottawa Heart Institute, Ottawa, Ontario (Dr Higginson); Central Biochemistry Laboratory, University of Minnesota, Minneapolis (Dr Steffes); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (Drs Gordon and Proschan).

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